MULTIPLE SCLEROSIS PROGRAM

Mission:To improve the lives of patients suffering from multiple sclerosis.

Overview:
The Multiple Sclerosis (MS) Program at UCLA aims to improve the lives of MS patients by developing new therapies for MS. This is accomplished through basic science in neuroscience, genetics, and immunology, as well as highly advanced neuroimaging and electrophysiology. The overall goal of this cutting edge research is to translate basic research findings into new treatments for MS through novel therapeutic trials. Four translational clinical trials have been conducted by Dr. Voskuhl based on work originating in her research lab, with two of these trials involving many sites across the U.S.

The Research:
Research in the UCLA MS Program is the epitome of translational research whereby findings are taken from the basic science "bench to the bedside." Uniquely however, the UCLA MS program's basic research starts with clinical observations such that it is actually a "bedside to bench to bedside" approach. The MS Program aims to answer clinical questions in MS such as why the disease remits during pregnancy, why men are affected less often, and why inflammation gives way to neurodegeneration as the disease progresses. These questions are pursued with basic research, and their answers often lead to novel treatments in MS, which aim to reverse the natural history of the disease or capitalize on situations where the disease is known to be quiescent.

Dr. Rhonda Voskuhl is the Jack H. Skirball Chair in MS Research and is the overall director of the M.S. Program at UCLA. She is an internationally recognized expert in MS. Dr. Voskuhl designs and conducts clinical trials in MS based on basic research findings made in the most widely used model of MS, experimental autoimmune encephalomyelitis (EAE). The Voskuhl laboratory is focused on understanding basic mechanisms of inflammation, neurodegeneration and neural repair. Dr. Voskuhl's strength is her ability to do basic research at the cellular and molecular levels in the MS model, then to translate these basic findings into the design of novel treatment trials in MS patients. She has had two novel agents in four treatment trials for MS completed or underway based on basic research results from her laboratory. See UCLA Dept of Neurology's MS Clinical website for more information. One area of interest has been gender differences in autoimmunity and neurodegeneration with respect to the role of sex hormones and sex chromosomes. The Voskuhl lab has made the discovery that sex hormones (estrogen and testosterone) and sex chromosomes (XX and XY) each contribute to disease susceptibility and progression. These findings are suggesting candidate neuroprotective treatments for MS and potentially other neurodegenerative diseases. She has also extended these findings to other autoimmune diseases such as the role of such factors in lupus. Dr. Voskuhl has received numerous National Institutes of Health (NIH) and National MS Society (NMSS) grants, and is also working with private industry to develop next generation novel treatments. In 2013, she was one of five finalists for the Barancik Prize from the National MS Society, an award recognizing the Most Innovative MS Researcher in the World.

The major strength of the UCLA MS Research Program lies in its collaborations with basic scientists beyond the Program itself, and often beyond the UCLA Department of Neurology, to capture the extraordinary expertise of the UCLA Neuroscience community, focusing this tremendous pool of minds on finding a cure for MS. The UCLA Neuroscience community is truly extraordinary in its breadth and excellence. It holds within it a vast array of expertise and brilliance. The MS Program has had remarkable success in collaborating with experts in various areas to ask and answer questions in MS that would not have otherwise been thought of or made possible. Major collaborators from outside the MS program include, but are not limited to, the following:

Dr. Michael Sofroniew, Professor, Dept. of Neurobiology, UCLA, an expert in neuroscience, glial biology and genetic engineering of molecules in cells within the brain.

Dr. Thomas O'Dell, Professor, Dept. of Physiology, UCLA, an expert in synaptic plasticity and electrophysiologic function in the brain.

Dr. Arthur Arnold, Professor, Dept. of Integrative Biology & Physiology, an expert in the effect of sex hormone and sex chromosome effects on the brain.

To summarize the research of the UCLA MS Program, it is equipped with the ability to do a wide variety of research in MS ranging from animal models of MS to patients with MS. This wide ranging capability is strongly focused toward developing novel treatments for MS, with two basic findings having already reached the level of ongoing clinical trials in MS. Evidence of the research ability of the UCLA MS Program can be found in its track record of high levels of funding from the NIH and NMSS over the last 15 years. The UCLA MS Program was one of the first MS Programs awarded an MS Collaborative Center Award from the National MS Society with Dr. Voskuhl as the Principle Investigator. This Collaborative Award recognizes MS Programs that bring in collaborators from outside the MS field to apply their expertise to advance research in MS.

Teaching and Training:
The training of clinician scientists and basic scientists is an important mission of the MS Program. Numerous researchers have obtained their Ph.D. in Dr. Voskuhl MS laboratory, and countless UCLA undergraduates have worked in various MS program labs learning to do MS research over the last decades. The MS Program also partners with high school students in mentoring students in MS research. The MS Program provides education to medical students, physicians, physicians, scientists, health care professionals, and the public. Additionally, the program provides educational resources such as courses for community healthcare professionals.

Community Relations and Support:
The UCLA MS program owes much of its success to the philanthropic support it has received over the years for its highly innovative projects. Support of these highly innovative projects in their infancy has been critical in generating the results needed to later move "high risk" projects into more traditional mechanisms of funding from the NIH and NMSS. Philanthropic supporters have included, but are not limited to, the Jack H. Skirball Foundation, the Conrad N. Hilton Foundation, the Sherak Family Foundation, the Gustafson Foundation, DirecTV, the Safan Family Foundation, the Diamont Foundation, the Zamucen Foundation and the Elks Club. Without the support of these visionary partners, the achievements of the UCLA MS Program would not have been possible. For further information on how to partner with the UCLA MS program in finding the cure for MS, contact Patti Roderick at 310-267-1837.

Summary of the Estriol Treatment Trial in RRMS:

Presented at the American Academy of Neurology on April 29, 2014

This was a double blinded, placebo controlled trial conducted at 16 sites across the U.S. Eligible patients were female, between ages 18 and 50, with actively relapsing disease, and an Expanded Disability Status Scale (EDSS) score between 0 and 4.5. Women who were pregnant, breastfeeding, taking hormone replacement therapy, or taking oral contraceptives were excluded from the trial.

Patients were randomized to glatiramer acetate injections (20 mg/day) and oral estriol (8 mg/day) versus glatiramer acetate injections and placebo. Gynecologists examined the patients before, during, and after the study. Each patient was examined at three- to six-month intervals during the trial. Patients also underwent mammograms before and after the study. In addition, at baseline, three months, six months, 12 months, 18 months, and 24 months, the investigators measured participants' estriol levels, and assessed for relapses and disabilities.

A total of 82 patients received glatiramer acetate (Copaxone) plus estriol, and 76 patients received glatiramer acetate (Copaxone) plus placebo. Baseline characteristics were similar in both patient groups. Participants' mean age was approximately 38, and their mean EDSS score was 2.2. The treatment was safe and well tolerated. Estriol levels in serum were in a mid pregnancy range in the estriol plus glatiramer acetate treated group.

The primary outcome measure of annualized relapse rate was achieved after 12 months of treatment, with the relapse rate 47% lower among patients receiving estriol and glatiramer acetate as compared with patients receiving placebo and glatiramer acetate. Beyond month 12 of treatment, the group receiving estriol and glatiramer acetate continued to have few relapses and few gadolinium-enhancing lesions on MRI. Thus, their disease activity remained stable and low at 24 months. Participants receiving placebo and glatiramer acetate showed expected effects of this standard of care treatment on relapses by month 24. However, there remained a 32% reduction in relapses in the estriol plus glatiramer acetate group as compared to the placebo plus glatiramer acetate group at month 24.

By 12 months of treatment, scores on the widely used cognitive test, the Paced Auditory Serial Addition Test (PASAT), were significantly improved among patients receiving estriol and glatiramer acetate. After 12 months of treatment, patients receiving estriol plus glatiramer acetate continued to have high PASAT scores to the end of study at month 24, while participants receiving placebo plus glatiramer acetate began to show improved PASAT scores by month 24.

Frequently Asked Questions:

Did you design the study as a combination therapy in order to prevent participants from being on placebo only?

Yes. Since the primary outcome was relapses and since relapses occur less than every year in most patients, the treatment duration had to be at least 2 years. Since drugs are available for MS that reduce relapses, trials of 2 years duration usually do not have a placebo only treatment arm. Notably, trials which add on a new treatment to an FDA approved drug are much more challenging than past trials which compared a new treatment to placebo only. Indeed, all of the approved drugs for relapses in MS were originally approved based on their benefit as compared to placebo alone.
Evidence regarding how difficult combination trials can be comes from work by others in a large study combining glatiramer acetate (Copaxone) injections with interferon injections (Avonex). This study showed no additive clinical effects despite treatment for 3 years duration and having large sample sizes of 250-400 patients per treatment (Lublin, et. al., Annals of Neurology, 2013).
The estriol trial had 80 patients in each treatment group (Copaxone + Estriol vs. Copaxone + Placebo) and showed a significant clinical effect on relapses within only 12 months. This significant clinical effect with only 80 subjects per treatment arm is striking with respect to its timing and potency. Most of the approved MS drugs using sample sizes of this size could only find an effect on a surrogate marker of relapses (like MRI markers), with only a trend of an effect on relapses themselves.

Why did you select Copaxone as the disease modifying therapy for your study?

At the time that we designed our study, it was known that Copaxone takes a while to start working after one starts treatment. Specifically, after starting Copaxone treatment, it can take 6-9 months to reduce enhancing lesions on brain MRI by about 50%. This was in contrast to high dose interferons, (another option at the time), which takes about 1-3 months to reduce enhancing lesions by about 80%. Enhancing lesions on brain MRI were known to be a surrogate indicator of relapses. Thus, we hypothesized that we would have an opportunity to see an effect of adding on estriol to Copaxone on relapses, particularly within the first year of treatment in patients who had just started taking Copaxone. That is precisely what happened.

Are there plans to conduct any head to head comparator studies pitting estriol against Copaxone or any other DMT?

There are several options being weighed in regard to future studies of estriol as an add on to a currently approved MS drug or to use estriol by itself as a monotherapy. Such trials are not mutually exclusive and could both be done. Several factors will have a role in the ultimate design(s), including who funds each study. If a pharmaceutical company that makes a currently approved drug funds a study, then they might want to use estriol in combination with their drug in an attempt to increase overall efficacy. If another entity funds a trial, they may be interested in developing estriol as a monotherapy, essentially competing with currently approved drugs. Both studies are needed.

Do estradiol or estrone also have these positive effects on MS?

The effects of these other types of estrogens are not known since trials of these agents have not been published. The least is known about estrone, while more is known about estradiol since it is the estrogen of the ovulatory cycle and synthetic mimics of it can be found in oral contraceptives and hormone replacement therapy. In the MS model, estradiol treatment ameliorates disease if given at a high enough dose. The problem with using estradiol at a high dose is that it is a strong stimulator of estrogen receptor alpha (ER alpha), and it is known that high levels of ER alpha stimulation promotes breast cancer, uterine endometrial cancer and blood clotting. Thus, it is unlikely that estradiol can be used at a high enough dose in MS to reduce MS disease without having toxic side effects. When oral contraceptives (OCPs)were assessed for their effects on MS incidence, no effect was shown, but in that study the dose of estrogen was not considered, with some OCPs even being progesterone only with no estrogen. Even "low dose" estrogen containing OCPs contain levels of estradiol that are far below pregnancy levels. They must in order to be safe. There is no solid evidence that such low doses of estradiol as in OCPs offer any significant disease modification in MS. Estriol, on the other hand, is unique in that it is not an estrogen of the ovulatory cycle, but is made only during pregnancy. It binds to ER beta more than to ER alpha. ER beta stimulation is known to counter toxic effects of ER alpha stimulation. Thus, a balance is achieved whereby toxic effects are avoided with estriol treatment based on preferentially binding to ER beta over ER alpha. Indeed, estriol has been known to be the safest of the estrogens for decades where it was used widely in Europe and Asia for HRT. It was generally used however at only 2 mg per day and our study has used estriol at a higher dose (8 mg/day) to induce a late pregnancy level in the blood. There were some previous studies that used estriol at 8 to 16 mg per day for HRT, so evidence for safety at 8mg/day exists. However large data sets of post marketing experience at 8 mg per day are not yet available. Notably, new drugs developed for MS generally come with no post marketing experience, with safety assessed only during trials. Often unexpected toxicities arise in trials of these agents. In our pilot estriol trial and in our multicenter estriol trial, both using 8mg per day, estriol treatment was safe. However, consultation with a gynecologist is always needed with estriol use, as should be the case with the use any estrogen.

Does menopause play a role in MS in women?

There is no evidence that loss of endogenous estrogen during menopause is associated with an increase in MS relapses. However, it remains unknown if menopause can play a role in MS worsening in terms of disability progression. Women with MS may do worse with regard to their MS during menopause, but there are other factors such as menopausal symptoms and aging that could contribute to the worsening. A controlled trial to test if estriol treatment may halt such worsening is needed. Interestingly, younger women who do not have MS and who undergo surgical menopause experience cognitive problems and these cognitive problems are improved with estrogen treatment. This suggests that endogenous estrogen of the ovulatory cycle could favorably affect cognition. This conclusion is supported by ovariectomy and estrogen replacement studies in healthy rats and mice. In these experiments, estrogen treatment causes prouting of new nerve fibers (axons and dendrites) and their connections (synapses) in cognitive areas of the brain. Such sprouting and reestablishment of connections has also been shown in mice with the MS model when they were treated with estriol. Further study is warranted to assess an effect of menopause and estriol treatment on cognitive problems and other disabilities in MS.

Can I start taking estriol now for my MS?

Estriol is not FDA approved in the U.S. so it is not available in pharmacies. It can be attained from compounding pharmacies, but these are not FDA regulated. To get FDA approval, another trial in MS must be done. We are raising money for that trial now and have a trial design ready for launch. Currently, prior to that study and prior to FDA approval, we cannot recommend that MS patients start taking estriol since efficacy for a given indication has not yet been proven in MS. We hope to get funding within the next 6 months, so the trial can be begin. The next trial could be completed within 3 years after its initiation.
There are fewer men diagnosed with MS than women and, from what I have understand, they appear to have a much more aggressive or progressive disease course. Is that true and if so, do male hormones play a role?
While men are less likely to get MS, when they get it, it tends to be more disabling or progressive in its course. This worse disability progression in men is not due to testosterone since we and others have shown that testosterone treatment is beneficial in MS models. Further, when we conducted a trial of testosterone treatment in men with MS to increase their blood levels of testosterone from low normal to high normal range, we found that testosterone supplementation significantly slowed brain atrophy on MRI, a biomarker of disability. Further, Bove et al. showed that men with lower testosterone levels have higher disability scores and do worse in cognitive testing over the subsequent two years. We are now raising money to do a larger, multicenter, placebo controlled trial of testosterone treatment in men with MS. The goal of the trial will be to prove that testosterone supplementation halts brain atrophy and slows disability accumulation in men. In addition, these men should experience the known beneficial effects of testosterone treatment including improved muscle mass and strength, less fatigue, improved sexual function, improved bone mineral density and an improvement in cognition as has been observed in elderly men. Why testosterone treatment halts brain atrophy and may halt disability progression is likely due to the fact that testosterone is converted to estrogen in the brain. While boosting testosterone levels in men with MS is very promising, until the next trial of testosterone treatment in MS men is funded and completed, we cannot currently recommend testosterone supplementation as a disease modifier in men with MS. The decision to take supplemental testosterone should be made in consultation with an internist and avoided in men with pre-existing prostate cancer or ischemic heart disease.
So the question remains, what makes MS men have a more rapid rate of progressive disability if it is not testosterone? Recently, we have published in the Proceedings of the National Academy of Sciences a paper showing an effect of sex chromosome gene expression in the brain using the MS mouse model. A gene on the X chromosome (Toll like receptor-7) expressed in cells in the brain (neurons) that can cause cell death during injury is expressed at higher levels in males (XY) versus females (XX) due to maternal imprinting of the one X gene in males. This may contribute to why MS men have a more progression course of disease, or respond worse to a given immune attack during MS. Finding new treatments to modulate this gene may lead to a treatment that will halt disease progression in both men and women with MS.

Why don't more groups study sex effects in disease?

This will soon change. The NIH recently announced that it is now implementing a new policy whereby sex differences in disease can no longer be ignored in NIH grants. This was published as a Nature paper in March of 2014, referencing our work in MS (3 of the total of 15 articles by Dr. Voskuhl and an additional 2 more by Dr. Arnold, her collaborator at UCLA), and discussing the estriol trial in the narrative as an example of success using this approach. Sex differences in disease lead to more than minor adjustments to doses medications depending upon whether one is female or male. Rather, sex differences in disease can hold major clues in understanding the basic pathogenesis of disease and thereby lead to novel treatments for both sexes. This novel conceptual approach has been spearheaded by Dr. Voskuhl and her collaborators for over a decade at UCLA.

Do women of childbearing age show any improvement in MS if they are on birth control?

No. see above. The type of estrogen used and the dose of estrogen is critical.

What are your next steps regarding basic and clinical research with estriol and MS?

In addition searching for funding to support the next estriol trial in women with MS (and the next testosterone trial in men with MS), we are well into the development of a "next generation estriol" that will bind only to ER beta receptor, with no binding to ER alpha receptor. This could be used in the subset of MS women at higher risk for breast cancer, uterine cancer or blood clotting since it would not bind to the estrogen receptor that contributes to these toxicities. Phase I trials are soon approaching to test our lead ER beta ligand in MS. Basic science into why estriol and testosterone have neuroprotective effects are a major goal. The major unmet need in the MS field is to find a neuroprotective treatment for MS. Once the first neuroprotective treatment is discovered, it can be unraveled and understood so that many more can follow. Thus, we are aggressively pursuing the precise cells and pathways involved in the neuroprotective effects of estriol and testosterone in MS.

Can estriol potentially be useful in other diseases?

Other autoimmune diseases which are known to improve during pregnancy, such as rheumatoid arthritis and psoriasis warrant investigation of estriol as a treatment in the form of a clinical trial.
Other neurological disease, particularly those which involve cognitive decline, such as Alzheimer's disease or cognitive decline associated with menopause, each warrant investigation of estriol as a treatment in the form of a clinical trial.

What other research endeavors are active in your lab?

SUMMARY of PROJECTS in the Voskuhl lab: THE NEXT STEPS

1. In addition to raising $15 million and designing the next estriol trial as required by the FDA to bring estriol to the market in the U.S., we are actively involved in the following other areas of research.

2. In our recently completed multicenter trial of estriol in women with MS where we found significant beneficial effects on relapses and cognition, we acquired brain MRI scans. These MRI scans now need to be assessed for whether estriol treatment slowed or halted gray matter atrophy, a biomarker for permanent disability including cognitive function. Funds needed: $250,000

3. A trial focusing on whether estriol treatment can improve cognition in not only RRMS, but also in progressive MS is needed. We have begun that trial, and it is ongoing at 4 sites across the U.S. Based on our results in the relapse trial, we know that this new trial is on target with regard to its optimal design and outcomes. In this trial, estriol treatment can be added on to other standard of care MS treatments (not just Copaxone, but also interferons or the new orals) or estriol can be used in people on no other MS treatments. The treatment duration is one year, and the primary outcome is cognitive testing. Based on data collected thus far, we now have an exact number with regard to how many patients are needed for that trial. It needs to be expanded and more clinical sites are needed. Funds needed: $900,000.

4. Given our extremely promising data from trials of estriol for women and testosterone for men with MS with respect to identifying an MS treatment that is not merely anti-inflammatory via suppressing immune cells in the blood, but rather one that can go to the brain to bind cells therein (astrocytes, oligodendrocytes, neurons, microglia) to provide neuroprotection and/or neural repair, we are aggressively continuing our pursuit of how these treatments work. Once the first neuroprotective drug for MS is established, understanding its mechanism of protection will lead to more drugs in the future targeting this mechanism. Funds needed: $500,000

5. As mentioned above, we are planning and raising funds for a large multicenter trial of testosterone treatment for men with MS. Funds needed: $8 million

6. Using the MS model in basic science experiments, we have identified a gene on the X chromosome that is expressed in the brain that may help us understand why men tend to have a more progression course of disease. Finding new treatments to regulate this gene may lead to a treatment that will halt disease progression, with relevance to other neurodegenerative diseases that demonstrate gradual progressive worsening. Funds needed: $400,000.

7. Using the MS model in basic science experiments, we have identified a gene on the X chromosome that is expressed in immune cells that may contribute to why women are more susceptible to developing MS and what contributes to relapses. Finding new treatments to modulate this gene may lead to a treatment that will reduce relapsing disease, with relevance to other autoimmune diseases characterized by an increased susceptibility in females. Funds needed: $400,000

8. Consistent with this focus on finding ways to halt disease progression, we are now dissecting through neurological pathways in the MS model to discover disability specific generic treatments for MS. This work is currently funded by the Conrad N. Hilton Foundation.

In conclusion, thank you for your interest in our MS research which is driven by clinical observations, which are unraveled and understood at the laboratory bench, leading to new treatments in the form of clinical trials. This is our MISSION: Bedside to Bench to Bedside research that leads to new treatments to halt MS, with relevance to other autoimmune and neurodegenerative diseases. Thank you for your time and consideration of our mission. Thank you for your support.